1. Field of the Invention
The invention relates to a process for producing a hydrophobic membrane using a thermally induced phase separation process, the membrane having a sponge-like, open-pored, microporous structure. The invention relates further to a hydrophobic integrally asymmetrical membrane that is suited in particular for gas exchange and is composed primarily of at least one polymer selected from the group of polyolefins and has first and second surfaces, the membrane having a support layer with a sponge-like, open-pored, microporous structure and adjacent to this support layer on at least one of the surfaces a separation layer with denser structure, and to the use of such a membrane for blood oxygenation.
2. Description of the Related Act
In a multitude of applications in the fields of chemistry, biochemistry, or medicine, the problem arises of separating gaseous components from liquids or adding such components to the liquids. For such gas exchange processes, there is increasing use of membranes that serve as a separation membrane between the respective liquid, from which a gaseous component is to be separated or to which a gaseous component is to be added, and a fluid that serves to absorb or release this gaseous component. The fluid in this case can be either a gas or a liquid containing the gas component to be exchanged or capable of absorbing it. Using such membranes, a large exchange surface can be provided for gas exchange and, if required, direct contact between the liquid and fluid can be avoided.
An important application of membrane-based gas exchange processes in the medical field is for oxygenators, also called artificial lungs. In these oxygenators, which are used in open-heart operations, for example, oxygenation of blood and removal of carbon dioxide from the blood take place. Generally, bundles of hollow-fiber membranes are used for such oxygenators. Venous blood flows in this case in the exterior space around the hollow-fiber membranes, while air, oxygen-enriched air, or even pure oxygen, i.e., a gas, is passed through the lumen of the hollow-fiber membranes. Via the membranes, there is contact between the blood and the gas, enabling transport of oxygen into the blood and simultaneously transport of carbon dioxide from the blood into the gas.
In order to provide the blood with sufficient oxygen and at the same time to remove carbon dioxide from the blood to a sufficient extent, the membranes must ensure a high degree of gas transport: a sufficient amount of oxygen must be transferred from the gas side of the membrane to the blood side and, conversely, a sufficient amount of carbon dioxide from the blood side of the membrane to the gas side, i.e., the gas flow or gas transfer rates, expressed as the gas volume transported per unit of time and membrane surface area from one membrane side to the other, must be high. A decisive influence on the transfer rates is exerted by the porosity of the membrane, since only in the case of sufficiently high porosity can adequate transfer rates be attained.
A number of oxygenators are in use that contain hollow-fiber membranes with open-pored, microporous structure. One way to produce this type of membrane for gas exchange, such as for oxygenation, is described in DE-A-28 33 493. Using the process in accordance with this specification, membranes can be produced from meltable thermoplastic polymers with up to 90% by volume of interconnected pores. The process is based on a thermally induced phase separation process with liquid-liquid phase separation. In this process, a homogeneous single-phase melt mixture is first formed from the thermoplastic polymer and a compatible component that forms a binary system with the polymer, the system in the liquid state of aggregation having a range of full miscibility and a range with a miscibility gap, and this melt mixture is then extruded into a bath that is substantially inert with respect to, i.e., does not substantially react chemically with, the polymer and has a temperature lower than the demixing temperature. In this way, a liquid-liquid phase separation is initiated and, on further cooling, the thermoplastic polymer solidified to form the membrane structure.
An improved process for producing such membranes, which permits specific adjustment of the pore volume, size, and wall, is disclosed in DE-A-32 05 289. In this process, 5-90% by weight of a polymer is dissolved, by heating to above the critical demixing temperature, in 10-95% by weight of a solvent system of first and second compounds, which are liquid and miscible with each other at the dissolving temperature, to form a homogeneous solution, whereby the employed mixture of polymer and the cited compounds has a miscibility gap in the liquid state of aggregation below the critical demixing temperature, the first compound is a solvent for the polymer, and the second compound increases the phase separation temperature of a solution consisting of the polymer and the first compound. The solution is then given shape and, by cooling in a cooling medium consisting of the first compound or the employed solvent system, is brought to demixing and solidifying of the high-polymer-content phase, and the cited compounds are subsequently extracted.
The membranes disclosed in accordance with DE-A-28 33 493 or DE-A-32 05 289 have an open-pored, microporous structure and also open-pored, microporous surfaces. On the one hand, this has the result that gaseous substances, such as oxygen (O2) or carbon dioxide (CO2), can pass through the membrane relatively unrestricted and the transport of a gas then takes place as a Knudsen flow, combined with relatively high transfer rates for gases or high gas flow rates through the membrane. Such membranes with gas flow rates for CO2 exceeding 5 ml/(cm2*min*bar) and for O2 at approximately the same level have gas flow rates that are sufficiently high for oxygenation of blood.
On the other hand, however, in extended-duration use of these membranes in blood oxygenation or generally in gas exchange processes with aqueous liquids, blood plasma or a portion of the liquid can penetrate into the membrane and, in the extreme case, exit on the gas side of the membrane, even if in these cases the membranes are produced from hydrophobic polymers, in particular polyolefins. This results in a drastic decrease in gas transfer rates. In the medical area of blood oxygenation, this is termed plasma breakthrough.
The plasma breakthrough time of such membranes, as producible in accordance with DE-A-28 33 493 or DE-A-32 05 289, is sufficient in most cases of conventional blood oxygenation to oxygenate a patient in a normal open-heart operation. However, the desire exists for membranes with higher plasma breakthrough times in order to attain higher levels of safety in extended-duration heart operations and to rule out the possibility of a plasma breakthrough that would require immediate replacement of the oxygenator. The aim, however, is also to be able to oxygenate premature infants or in general patients with temporarily restricted lung function long enough until the lung function is restored, i.e., to be able to conduct extended-duration oxygenation. A prerequisite for this is appropriately long plasma breakthrough times. A frequently demanded minimum value for the plasma breakthrough time in this connection is 20 hours.
From EP-A-299 381, hollow-fiber membranes for oxygenation are known that have plasma breakthrough times of more than 20 hours, i.e., there is no plasma breakthrough even under extended use. With the otherwise porous membrane, this is attained by a barrier layer that has an average thickness, calculated from the oxygen and nitrogen flow, not exceeding 2 xcexcm and is substantially impermeable to ethanol. The membrane is substantially free of open pores, i.e., pores that are open both to the outside and to the inside of the hollow-fiber membrane. According to the disclosed examples, the membranes in accordance with EP-A-299 381 have a porosity of at most 31% by volume, since at higher porosity values the pores are interconnected and communication occurs between the sides of the hollow-fiber membranes, resulting in plasma breakthrough. In the barrier layer, the transport of gases to be exchanged occurs by solution diffusion.
The production of these membranes is conducted via a melt-drawing process, i.e., the polymer is first melt-extruded to form a hollow fiber and then hot- and cold-drawn. In this case, only relatively low porosity values are obtained, which means that, in conjunction with the transport occurring in the barrier layer via solution diffusion, the attainable transfer rates for oxygen and carbon dioxide remain relatively low. Moreover, while the hollow-fiber membranes in accordance with EP-A-299 381 exhibit sufficient tensile strength as a result of the pronounced drawing in conjunction with manufacture, they have only a small elongation at break. In subsequent textile processing steps, such as producing hollow-fiber mats, which have proven excellent in the production of oxygenators with good exchange capacity and as are described in EP-A-285 812, for example, these hollow-fiber membranes are therefore difficult to process.
Typically, in melt-drawing processes, membranes are formed with slit-shaped pores with pronounced anisotropy, the first main extension of which is perpendicular to the drawing direction and the second main extension perpendicular to the membrane surface, i.e., in the case of hollow-fiber membranes, runs between the exterior and interior surfaces of the membrane, so that the channels formed by the pores run in a relatively straight line between the surfaces. In the case in which, for example, mechanical damage in the spinning process causes leaks in the barrier layer, a preferred direction then exists for the flow of a liquid between the interior and exterior surfaces or vice-versa, thereby promoting plasma breakthrough.
It is therefore an object of the invention to provide a process with a wide variety of applications and with which integrally asymmetrical membranes with a microporous support structure and a separation layer with denser structure can be produced that are suited for gas exchange and that exhibit at least to a reduced extent the disadvantages of the prior art membranes, permit high gas exchange capacity, are impervious at least over extended periods of time to a breakthrough of hydrophilic liquids, in particular blood plasma, i.e., are suited in particular to extended-duration oxygenation, and have good qualities for further processing.
It is a further object of the invention to provide membranes in particular for gas exchange in which the disadvantages of the prior art membranes are at least reduced, that have a high capacity for gas exchange and sufficiently high gas flow rates for blood oxygenation, are resistant at least over extended periods of time to the breakthrough of hydrophilic liquids, in particular blood plasma, and exhibit good qualities for further processing.
The object is met by a process for producing an integrally asymmetrical hydrophobic membrane having a sponge-like, open-pored, microporous support structure and a separation layer with a denser structure compared to the support structure, the process comprising at least the steps of:
a) preparing a homogeneous solution of 20-90% by weight of a polymer component consisting of at least one polymer, selected from the group of polyolefins, in 80-10% by weight of a solvent system containing a compound A and a compound B that are liquid and miscible with each other at the dissolving temperature, whereby the employed mixture of the polymer component and compounds A and B has a critical demixing temperature and a solidification temperature and has a miscibility gap in the liquid state of aggregation below the critical demixing temperature, and whereby a solvent for the polymer component is selected for compound A, and compound B raises the demixing temperature of a solution consisting of the polymer component and compound A,
b) rendering the solution to form a shaped object, with first and second surfaces, in a die having a temperature above the critical demixing temperature,
c) cooling of the shaped object using a cooling medium, tempered to a cooling temperature below the solidification temperature, at such a rate that a thermodynamic non-equilibrium liquid-liquid phase separation into a high-polymer-content phase and a low-polymer content phase takes place and solidification of the highpolymer-content phase subsequently occurs when the temperature falls below the solidification temperature,
d) possibly removing compounds A and B from the shaped object, characterized in that a strong solvent for the polymer component is selected for compound A, for which the demixing temperature of a solution of 25% by weight of the polymer component in this solvent is at least 10% below the melting point of the pure polymer component, that a weak non-solvent for the polymer component is selected for compound B, which does not dissolve the polymer component to form a homogeneous solution when heated to the boiling point of compound B and for which the demixing temperature of a system consisting of 25% by weight of the polymer component, 10% by weight of the weak non-solvent, and 65% by weight of compound A, used as a solvent, is at most 8% above the demixing temperature of a system consisting of 25% by weight of the polymer component and 75% by weight of compound A, and that, for cooling, the shaped object is brought into contact with a solid or liquid cooling medium that does not dissolve or react chemically with the polymer component at temperatures up to the die temperature.
Surprisingly, it has been shown that, by adhering to these process conditions, integrally asymmetrical membranes are obtained in which at least one surface is formed as a separation layer, which has a denser structure compared to the support layer structure and covers the adjacent sponge-like, open-pored, microporous support layer structure. The process according to the invention allows the realization of separation layers with very thin layer thickness, whose structure can be adjusted down to a nanoporous structure with pores at most 100 nm or to a dense structure. At the same time, the support layer of the membranes produced in this manner has a high volume porosity. Preferably, using the process according to the invention, integrally asymmetrical membranes are produced with a dense separation layer. In the context of the present invention, a dense separation layer is understood to be one for which no pores are evident based on an examination by scanning electron microscope at 60000xc3x97magnification of the membrane surface having the separation layer.
The process according to the invention thus permits the production of integrally asymmetrical membranes with a separation layer that renders the membranes impervious over long periods of time to liquid breakthrough but at the same time gas permeable, and with a support layer with high volume porosity, resulting at the same time in high gas transfer capacity for these membranes in gas transfer processes.
The object is therefore further met by a hydrophobic integrally asymmetrical membrane, in particular for gas exchange, that is composed substantially of at least one polymer selected from the group of polyolefins and has first and second surfaces, the membrane having a support layer with a sponge-like, open-pored, microporous structure and adjacent to this support layer on at least one of its surfaces a separation layer with denser structure, characterized in that the pores, if any, in the separation layer have an average diameter  less than 100 nm, that the support layer is free of macrovoids and the pores in the support layer are on average substantially isotropic, and that the membrane has a porosity in the range from greater than 30% to less than 75% by volume and a gas separation factor xcex1(CO2/N2) of at least 1.
These membranes find excellent application for blood oxygenation, whereby the separation layer of these membranes is responsible for making these membranes impervious over extended periods of time to the breakthrough of blood plasma.